Salomon is an associate professor in the Department of Molecular and
Experimental Medicine at the Scripps research Institute in La Jolla,
California, and chair of the FDA's Biological Response Modifiers Advisory
Committee. He also serves on the Secretary's Advisory Committee on
Xeno-transplantation. While he believes maintaining public safety is paramount
to moving forward with xeno-transplantation, he also argues "If you regulate the
technology out of existence before the technology has shown any evidence of its
promise, then you've robbed future generations of a tremendous boon."
(Interviewed Winter 2001.)

What is the promise of this technology?

Xenotransplantation, the ability to transplant tissues, cells, and organs from
animals, is a tremendous scientific advance. Basically, it allows us to have
an almost unlimited supply of organs for transplantation. But even more
importantly, it gives you an almost unlimited supply of cells. . .

The stakes are huge. Right now, there are about 60,000 patients waiting for a
kidney transplant. They're on the waiting list for up to four or five years
before they can even see a transplant these days. There are patients dying
every day from a need for an organ like a heart or a lung or a liver.

So those patients could be saved almost immediately. But even more
importantly, rather than having to be so sick that they're in an intensive care
unit on death's door, these people could be transplanted very early in their
disease, and the effects on these people and on their families, the amount of
suffering reduced, is just incredible to think about.

On the other hand, with cellular transplantation, there are a million and a
half diabetic children in the United States alone. You're never going to touch
that need with human organ donation. Only something like cell transplantation,
only something like xenotransplantation is going to address this incredible
health need.

So the promise of xenotransplantation extends over a remarkably broad group of
people and diseases. It can go anywhere from end-stage kidney disease, liver
disease, and heart disease to multiple sclerosis, stroke, and diabetes. The
impact of the successful therapy based on xenotransplantation will be
tremendous.
If it works, how big a breakthrough could it be?

I think that xenotransplantation as a success would provide a therapy that
would give us unlimited tissues and organs for transplantation. Therefore, we
could apply it very early in the stage of disease, long before the kind of
suffering and risk of death that is routinely a part of organ transplantation
today.

In terms of cell transplantation, the impact is there that we could even do it
at all, because at the current time, the amount of tissues available for this
sort of thing, say for cell transplantation for diabetes mellitus, is not even
close to being able to fulfill the need. Xenotransplantation then creates a
whole opportunity to treat a group of patients that, right now, we couldn't
even treat.

. . . I think what's remarkable is to think of this as a continuum. There's
xenotransplantation. But the incredible successes of the human genome project
now allow us to see life and disease as part of a molecular phenomenon, as part
of genes functioning and dysfunctioning in the body. And to the extent that
these are connected, that we're going to have to deliver gene therapy, we're
going to have to deliver on this incredible promise of the human genome project
-- xenotransplantation, cell transplantation, gene transplantation, which, in a
way, are all linked. When you put them together, and consider them as a
continuum, our ability to reach out and treat a remarkable range of diseases
becomes real.
What does xeno mean for us in terms of a breakthrough in technology? Does
it have the potential to change, in fundamental ways, how we do
medicine?

First of all, xenotransplantation has aspects of it that are an outgrowth of
conventional human-human organ transplantation. What's fascinating, however,
is that a simple application of what we're doing in human-human organ
transplantation is not working for xenotransplantation. In other words,
there's a series of fundamental barriers that are added by xenotransplantation.
And that's the challenge right now to solve.

Now, in the process of solving them, we're gaining very important insights that
I believe will also be applicable back to human-human organ transplantation.
There are a lot of things that we're learning about how the immune response
deals with blood vessels, for example, and why injury occurs to blood vessels,
that I think will be extremely important in an understanding of chronic
rejection. Right now, that is one of the biggest challenges in human-human
organ transplantation. So certainly advances in xenotransplantation, just like
in many areas of medicine, will drive other advances -- some advances that one
can't even anticipate at this point.

There are some other remarkable features that are unique to
xenotransplantation. It is going to be the first area in which genetic
engineering of animals, of animal tissues in order to get a desired effect
after the transplant, is actually going to be tested in principle. Success
there then becomes a model for genetic engineering of any sort of cell or
tissue transplant. And in the end, that could be human stem cells being
engineered, for example, and that gets back to this whole excitement over the
human genome project that's now very public. Delivery on the promise of the
human genome project will require genetic engineering. And genetic engineering
is now being tested for the very first time in xenotransplantation. So it's
all linked in an exciting development.
How fundamental a change are we looking at? In terms of breakthrough, how
could it change medicine and how we practice it?

Successful xenotransplantation would essentially create a set of options for
practicing physicians that would extend over such a remarkably broad range of
diseases that it would fundamentally change the practice of medicine now, and
in the foreseeable future.

Presently, when faced with the deterioration of organ systems, we really are
obligated to spend years, literally, with all kinds of medications. And as
things get more serious, we use increasingly toxic medication regimens, trying
to keep the patient's system functioning, to keep the patient alive, to keep
the patient as healthy as possible.

But the reality is that the tradeoffs are tremendous for those patients, and
they're negative. The patients are never as healthy as they could be. A lot
of them just can't work. They certainly can't enjoy their lives or their
families and do the kinds of things that they want to do. So they pay a
tremendous price for our inability to intervene in their diseases at the most
fundamental level, and that is to basically replace diseased tissues and
systems.

Xenotransplantation is part of the future of medicine in which, very early in
this inexorable process of deterioration of tissues and organs, one could step
in definitively and successfully and cure it. No toxic regimens. One could
cure it.
What's the big challenge? What's the big hurdle to get over in
xenotransplantation?

One of the problems in xenotransplantation has been a tendency to oversimplify.
To think about xenotransplantation as having a single barrier -- you get over
the single barrier, and then you've got a successful transplant program. And
earlier, that led a lot of people about five, six, seven years ago to predict
that, because their view was that there was only one big barrier, hyperacute
rejection -- the fulminant immune response and destruction of the graft. If
you got over that, these people argued, it would be just like human-human
allotransplantation. And we'd suddenly see 80%-90% one-year graft survival and
75%-80% two- and five-year graft survival.

Great. But that's not what happened. And then a number of people had to go
back and explain to the public why xenotransplantation wasn't working. And in
the end, it didn't really serve the purpose that it was intended to do, to get
people excited and to move the field forward.

So is there a single barrier to xenotransplantation? No, I don't really
believe so. I believe there's a whole series of barriers. In the end, these
are animal organs going into humans. And one cannot ignore the importance of
evolution. I mean, we've spent a lot of years as human beings evolving our
systems away from the level we were at when we were back at the level of pigs.
We're going to have to realize that the biology of pigs is fundamentally
different than the biology of humans. And all of that's a barrier to
successful xenotransplantation.
So in summary, what is the little voice of caution that you would
add?

I think that the reality here is that in organ transplantation, we're really
not there yet. The data suggests that we're talking about a month to maybe a
month and a half, maybe one guy out of ten is claiming two months' survival of
any sort of organ in a legitimate model for xenotransplantation. That's not
going to work. Patients are not going to undergo any of these sort of
tremendous risks, surgery, pain, suffering, and recovery for an organ that's
going to function for a month or two. It's common sense. It isn't ready for
primetime. This is still a work in development. This is research.

Now, in cell transplantation, it's different. In cell transplantation, we're
actually ready. There is some success in cell transplantation. A lot more
needs to be seen in order to really see the future and the promise of it. But
at least it's ready to be tested in limited numbers of patients.
How far off are we from seeing the first clinical full organ
xenotransplant...?

The honest answer is that I really don't know. If one takes the view I have,
that there are multiple barriers and you only see the next barrier when you
overcome the one before it, then it's really hard to guess. I would suspect
that they'll be able to move forward perhaps sometime in the next five to ten
years.
So what does the public need to know about this?

Xenotransplantation as a new technology is breaking some scientific ground.
It's also breaking ethical ground. And at all those levels, public discussion
and public understanding is critical. From a new scientific ground, we're
talking about genetic engineering of animals. We're well aware of the public's
fears and concerns over genetic engineering of anything living, including
plants. And we have to respect that concern, address it, discuss it with the
public, and include them in the process of moving this field forward.

Xenotransplantation will involve large-scale herds of animals. We accept this
sort of thing in most of the developed world for food -- cattle, pigs,
chickens, etc. But there are some significant ethical issues for raising
animals for food, and equally significant issues of raising genetically
engineered animals for healthcare. And again, the public should be a part of
that discussion, and it's important.

There are also risks that are inherent in xenotransplantation, risks that we
are just now beginning to define, risks of viruses, and possibly other animal
infectious agents that could be moved from animals to humans in the process of
transplantation. The public is very aware of this. They're aware of flu
epidemics that threaten public health. They're aware of mad cow disease that
comes possibly from eating certain kinds of infected beef.

Once again, the public deserves a discussion of the risks of transplanting
animal organs into human patients, particularly at the moment, animal organs
into human patients who are receiving lots of drugs to suppress their immune
response.
What about the idea of consent -- not just from the patient or participant
involved -- but the potential that some of these viruses could become a public
health factor?

I think one of the fundamental things in xenotransplantation, because of the
possibility that one might move an infectious agent from an animal organ
transplanted into a human, is that consent now has to be looked at in a new
way. If a consent is obtained from an individual and the risk is to the
individual, then consent is theoretically possible. The individual can
consent, even risk their life, if there is a perceived benefit that it may save
their life.

The game is totally different if it's possible that, in the process of saving
this patient's life, I transmit an infection into that patient that now would
be transmitted to his wife, his children, or any of our children. The idea
that there is a public health risk inherent in xenotransplantation changes the
consent process dramatically. One can consent for yourself; you cannot consent
for the public. In that sense, public discussion, public review, public
debate, is the public's part of the consent process for xenotransplantation.
How do you get public or societal consent for something like this?

Well, the actual truth is that you're never going to get public consent for
this. And in fact, the idea that you're going to get public consent is
something that's been manipulated by some people. What scientists and
physicians are obligated to do in xenotransplantation or in gene therapy or any
new cutting-edge technology is, frankly, to outline for the public the spectrum
of risks, the spectrum of benefits, to help the public comprehend what we call
a risk-benefit ratio. And in the context of an intelligent discussion of risk
and benefit, allow the public to see what the ethical world is around those
problems, contribute, discuss, ask questions, understand. That, to me, is the
purpose of public discussion.
How does one answer those doctors who bring us their desperate and often
dying patients as an example of their enthusiasm to see xenotransplantation?
They say things that show that they're incredibly confident that the costs of
this outweigh any concerns that the public may have on any level. How does one
answer that?

I greatly respect the passion and the dedication of these physicians to their
patients. Frankly, that's what patients should expect from their physicians,
and no less. . . .

However, there are other points of view. There are others in this spectrum of
debate who make a very critical point that there are risks here -- risks to the
public -- risks of bringing an infection into the public which could be as
serious as the AIDS epidemic. This is just as serious, and they're just as
passionate.

The appropriate response to both these extremes and what the public expects
from science is that we define the extremes and then go to the laboratory; do
the basic research; do the clinical research; answer the questions; and then
come back to the public.

At a certain point, all the handwaving and dramatics from either end of the
spectrum have done their job, and it's over. It's time to get facts, to come
back to the public, to give the public the facts based on science. That's what
the public supports research for.
Can one quantify the risks in xenotransplantation?

We can quantify the risks of xenotransplantation, provided we have enough
scientific information based on rigorous models for xenotransplantation
infection risk, and eventually very carefully acquired experience in clinical
medicine. But yes, eventually we can quantify the risk.
Can we quantify the risk right now?

No. Presently what we can say with surety is that there is a risk of
infectious disease in xenotransplantation. There is a risk of transmitting
infectious agents from animal organs to human patients during a transplant. We
can also say that there is a risk that those infectious agents will move from
the patient to the public. It's real that there is a risk to both the patient
and to the public. So in that context, there is a risk.

What we can't say is the dimension of the risk. There are people who will tell
you it's very, very small, and others who will tell you it's very, very large.
The truth, in my opinion as a scientist in this field, is that we just can't
quantify the risk right now.
What should the public do then right now? If we can't quantify the risk . .
.

In the last four or five years, the public, in partnership with governmental
regulatory agencies like the FDA, the NIH, and the CDC, and scientists and
physicians in xenotransplantation have done a very good job of defining the
issues. They've showed the spectrums, from the impassioned physician who needs
to save the patients who are dying to the others that are concerned about a
catastrophic health consequence -- public health epidemics -- from this.

So we've defined the issues. And now what should the public do? Nothing. The
public should wait while we do the science that we owe the public to fill in
the gaps; to provide knowledge and results upon which to come back to the
public; and to reenter the debate, but with more knowledge.
What's pushing xeno forward?

. . .For the physicians with sick and dying patients, the pressure's
obvious. They want their patients to be healthy. They want new ways to treat.
For drug companies and biotechnology companies, the stakes are equally huge,
because this is a market that's tens of millions of people, and they realize
it. And it's okay, because right now, that money that these companies are
willing to invest is driving the field forward toward the success that everyone
is so excited about. There's nothing wrong, in my opinion, with drug companies
and biopharmacology companies having a reasonable expectation that they will
profit if their investment in xenotransplantation is successful.
So should we barrel ahead and order up clinical trials?

No. From a regulatory point of view, there has to be a balance. There has to
be a group empowered to review the data as it comes out, and objectively decide
when it's time to go forward with specific xenotransplantation procedures.
You're breaking brand new ground. There's going to have to be an inspired
balance, if you will, between allowing a field to move forward into absolutely
brand-new territory and yet, at every point along the way, ensuring that safety
is utmost in the minds of the scientists and physicians doing these studies.

I think that that kind of balance is perfectly possible. We've moved forward
with gene therapy under those guises; we've moved forward with new drugs, new
vaccine trials.

So, from a regulatory point of view, there is already a very well defined
regulatory context established by the Food and Drug Administration in
partnership with the National Institutes of Health and the Centers for Disease
Control in Atlanta. And it's all being overseen by the secretary of health and
human services at the presidential cabinet level. So I think that we're in a
pretty good situation right now, having a strong regulatory oversight to help
guide xenotransplantation safely through the first clinical trials.

Right now, trials are going forward in xenotransplantation with cells--not
organ transplantation. But we're moving forward right now with cell
transplantation, specifically with pig cells. We're also exposing some
patients to pig cells by circulation outside the body. In these instances,
some people argue that with cell transplantation, because the dose is smaller,
the dose of potential virus exposure is smaller, that there would be less risk.
That might seem to be true, if you just think about the size of an organ versus
a few cells.

But the reality is that if a cell is transplanted and survives long-term and
day after day is putting out infectious virus, the risk is every bit as real as
a bigger organ surviving for the same period of time putting out a little more
virus everyday. Once you reach a threshold of infectious exposure, you get
infected. It doesn't matter if it's larger or smaller, if it gets over the top
of the threshold.
Can you talk about assessing risk and benefit?

The basic principle in regulation of a new technology is assessing risk and
benefit. And we talk about the risk-benefit ratio. To assess benefit for a
new therapy, we have to look at the disease the therapy is intended to benefit.

So let's take replacement of a failing kidney; let's take replacement of a
failing heart. What we expect is that someone who wants to move forward with a
clinical trial of human patients with xenotransplantation for a failing kidney
or heart demonstrates to the regulatory agency, and to other peers in the
field, that the heart or kidney that's being replaced will function for a
pretty reasonable period of time without destruction by the immune system.
That's what we would call benefit.

Now, of course, exactly how much benefit becomes somewhat of a judgment. We
have to remember that, in many ways, we're talking about benefit being
demonstrated in animal models of kidney failure and heart failure, and that
we're trying to figure out then from there what benefit would be for human
patients getting the same. And that's not a perfect process.

But within reason, there have been very high-level discussions in the
regulatory agencies and the subcommittees of the FDA on exactly defining what
the level of success would be. And we're nowhere near that today. But we have
a good idea where we want to be before we allow the first clinical trials.
What is the current criteria for evaluating benefit and getting approval for
going ahead with clinical trials to transplant pig organs into humans?

In the sense of defining what level of benefit a federal regulatory level would
allow us to go forward in clinical trials, there have been very detailed
discussions had at the FDA in the Subcommittee for Xenotransplantation. The
results of those discussions are that, for kidney and heart transplantation,
there should be approximately six months of life-sustaining function of
xenotransplanted organs without any evidence of a terrible destruction of those
organs at that time.

At the present time . . . the facts are that for kidney transplantation, we're
talking about 45 days -- not even two months' survival -- of a kidney in a
life-sustaining model of kidney failure in an animal. And for heart
transplantation, it's approximately two months as well. So we're really quite
a bit short of achieving even the minimal benefit that we would consider
reasonable to justify clinical trials now.
What are the barriers?

What everybody understands today is that the first barrier to successful
xenotransplantation is hyperacute rejection, the fulminant destruction of an
organ by the immune system. We made progress. We've gone from survival of
organs for literally minutes to survival of organs for a month to two months.
This is a tremendous scientific success.

But patients undergoing a kidney transplant or a heart transplant are going to
expect their organs to last for years, not weeks. And so there really is a
tremendous gap yet to fill before we can go forward to clinical trials. It's
reasonable to hold back going to clinical trials until the science progresses
further.
As much as some want to move forward fast, what, in sum, are your
views?

Having participated in the discussions at the federal level, in the FDA's
Xenotransplantation Subcommittee meetings, having seen the data presented by
the different groups who are working on transplantation of organs into
different animal models, I agree with the current view that it is too early.
There's not enough benefit demonstrated in these animal models to justify going
forward in the clinical trials today. I think that we've made tremendous
progress. I believe that there is nothing standing in our way that can't be
solved by further scientific research. But we're not there yet.
Why have clinical trials anyway? What can you learn from human clinical
trials that you can't learn from animal trials?

I think a very important point to make to the public is that, while animal
models are extremely valuable in moving new technologies in medicine forward,
an animal is not a human. Of course that's obvious to everybody. So at some
point, we need to reassure the public that if medicine is going to move forward
responsibly to new therapies for disease, there has to be a point in which you
go from an animal trial to a human clinical trial.

And you have to accept the fact that, no matter how much energy and time you
spend perfecting your animal model, it's an animal model. And in the end,
we're treating patients; we need to know what happens in human patients. It's
important that we realize that there may be surprises in human patients, and
we'd better be prepared for that, too.
What are the issues involving the patient's informed consent?

. . . At a regulatory level, because of the possibility of moving an infectious
agent from the animal organ to the human, and because of the possibility that
it might move from the patient to the family, we have broached some really new
ground. We're talking in terms of asking not only the patient, but also the
patient's family, to basically consenting to a long-term follow-up.

We're talking about years during which we would take blood samples, we would
monitor their clinical course, we would look for any unusual sorts of diseases
or complaints that might give us the first clue of a possible infectious agent
that we didn't predict. We would actually get blood samples from the nearest
relatives, the wife or husband and the children of these patients. We would
not allow them to give blood or semen or other tissues for donation, as many
public-spirited individuals are wont to do.

And it's very interesting, because there are really very few legal precedents
for what we're expecting a patient to do. Inherent in a consent, right in bold
black at the bottom of the consent, it has to say that, at any time, you can
withdraw from the trial. If we do a xenotransplant and six months later the
patient can withdraw from the trial, and we have no call to legally enforce
sampling of that patient for any infectious blood -- in fact, that patient
never has to report to us again; he can disappear, she can disappear -- it
raises some very interesting questions.

On one hand, we've gone to all these extents to reassure the public that we
have all these safeguards. We're going to do the testing and we're going to
follow the patient long-term and we're going to keep track of them and we're
really going to stay on top of it. And yet the truth is that, because of the
legalities of the consent process in the United States today, it really will
require a tremendous amount of voluntary participation by the patients and the
patient's family for this to work.
And what are we asking them, concerning long-term follow-up?

At the moment, the kinds of things being proposed for clinical trials of
xenotransplantation for long-term follow-up include at least yearly sampling of
blood, possibly saliva, possibly semen from patients, and also from intimate
contacts -- spouses and children. We are specifying that if the patient
develops any sort of disease during this period of time, that that information
be disclosed to the regulatory agencies -- not to the public, of course -- so
that symptoms of new diseases might be linked possibly back to the
xenotransplant.

We would very much like to be able to get permission for an autopsy if the
patient should pass away during the period of follow-up, and permission to do
experimental research on the tissues and the organs from that autopsy in order
to look for possible pig viruses. We'd want to look for anything that could
potentially have caused the death of that patient from the xenotransplant.
These are things that are way beyond the current definition of the universe for
a consent form today.
Can we ethically go there?

I think that here is an excellent example of where public discussion becomes
very critical to moving forward a new field. If the public can participate; if
the public can understand the tremendous importance of moving this technology
forward; if the public can understand the special nature of these changes to
the consent process as currently seen; if the public can support this sort of
movement forward as part of the guarantee of safety in an area like this; then
that's a very powerful message to the law-making organizations, such as
Congress in the United States, which would be responsible for changes in the
consent form.
Is it fair? Is it what we should do?

I believe that if we want to safely move a new technology like
xenotransplantation forward, we need to do whatever is necessary to ensure the
public's safety. In this case, it is to maintain long-term follow-up on all
the patients and intimate contacts of these patients.
So people have to understand that we're talking long-term here, and
we don't know how long it will take to manifest.

Right. To properly guarantee the safety of xenotransplantation for future
generations, what we're actually asking patients to do upfront is to agree to
follow-up for life. We're also asking for access to their tissues after death
for the kind of research studies that are going to be required to determine if
their death had anything at all to do with the xenotransplant. Even if the
death wasn't directly caused by the xenotransplant, if in this patient that
died there is any evidence for spreading infection or a tumor or any sort of
complication of xenotransplantation, then we owe that to the public and to all
future generations in the implementation of a new technology like this. The
contract with the patient is a remarkable one. It's one that literally is
unprecedented in medicine.

And there's definitely now the beginnings of a movement in Congress to
acknowledge the fact that part of the trade-off for guaranteeing safety in new
medical technologies is some dealing with the special issues of consent and
patient interactions that are involved.
What about the possibility of rogue experimental efforts in other
countries?

No matter how much effort we all spend regulating xenotransplantation, arguing
about the best way to protect the individual and protect future generations,
the stark reality of this world is that, for all our efforts, there are going
to be many areas of the world in which xenotransplantation could move forward
without any of this kind of regulatory oversight.

Now at this point, you might say, "Oh, yes, anything could happen." No. The
reality is that it is happening. We are aware of several what we call "rogue"
xenotransplantation programs in Europe and in Central and South America. Some
are being advertised on the worldwide web that are literally ready, for a fee,
to transplant a whole variety of animal organs to human patients for diseases
that range from aging to depression.

I actually had a phone call from a woman who, after some publicity on one of
the papers that we wrote on xenotransplantation and infection, called me and
asked me whether I thought it was okay for her to go to a special clinic and
undergo animal parts transplantation in order for rejuvenation, to protect her
beauty. And of course I explained to her that it wasn't okay, that it was a
very serious step and she should think about it very carefully, and I would
advise not going. But the fact is, this is happening now.
If human trials go forward and infection happens, how long could it take for
us to understanding if infection occurred?

If an infectious particle gets transmitted from a pig organ to a patient after
a point of transplantation, we could see things as early as days. But it could
also take several years. The idea of some of these new molecular testing
technologies we've developed is that, even though it might take years for us to
see clinical disease, evidence for viral replication would be evident very
early.

So we really don't think that it would take longer than three, four, or five
years max to get a pretty good idea of whether or not there was some really
overwhelming risk of infection in a human patient which was not anticipated in
the animal studies . . . that were done up to that.

. . . A key point, however, is that there's also the element of unknown. In
the last few years, there have been several new infectious diseases that came
from animals and were transmitted to humans, and we had no idea they existed
before they started. Certainly within the last several decades, we've seen the
AIDS epidemic come from monkeys in Africa to humans and then spread throughout
the world. As recently as a few years ago, a virus in Malaysia spread from
domestic pigs to people, killing literally hundreds of Malaysians before the
epidemic was stopped. We've also seen several recent outbreaks of Ebola virus,
which is probably also coming from a different group of monkeys in Africa.

So the point here is that it's always possible, when dealing with the unknown,
that an infectious event that was transmitted from the pig to the human during
a xenotransplant is not going to be covered by all our best efforts to have
these beautifully sophisticated molecular diagnostics. You can only make a
diagnostic for an agent that you know about.
What's the specific scenario involved here?

Well, the infectious risk presented by transplanting an animal organ into a
human has several different features. One is that we don't know enough about
how animal cells and animal tissues will behave in a foreign environment. In
other words, going from an animal environment to a human environment
potentially under attack by the immune system is obviously a very abnormal
situation to model.

In our own studies, we demonstrated, for example, that transplantation of pig
cells into another animal -- in our case, an immune-deficient mouse -- resulted
in the accelerated production of virus by those pig cells. And we demonstrated
that it was due to stress on the cells, as part of the transplantation
process.

So one feature that's unique to xenotransplantation is what sort of impact the
transplantation itself is going to have. Secondly, xenotransplantation, at
least as we currently are planning it, is going to involve immunosuppressives,
powerful drugs that prevent rejection of the new organ. Well, those are very
important for success, but they also suppress the patient's ability to fight
the infection.

The third major issue is that we're going to be genetically engineering animals
in order to enhance our potential for success in xenotransplantation. The
process of this engineering can also, and will also, have an impact on the
behavior of these cells in the new patient, as well as possibly on the
infectious nature of the virus.
Somebody says, "Forget about it. I want to opt out." What do you
do?

You mean after they've got the transplant? The reality today is that if a
patient signs a consent for a xenotransplantation trial, and decides at any
time after the xenotransplant to opt out, to say, "Forget about it," that is
within that patient's legal right, and there is at the moment nothing that we
could do.
Is it a problem?

Of course it's a problem. We just have spent so much time at the level of
federal regulatory agencies, reassuring ourselves and then selling to the
public the fact that we've done everything possible to protect present and
future generations from the risks inherent in this procedure. If patients
decide, after all of that, after all our best efforts, to simply opt out after
the transplant, of course it's a problem.

Now, there's another interesting part of the problem. There are no laws, right
now, to prevent a US patient from going to another country and receiving a
xenotransplant, and then getting an airplane the next day and flying back to
the United States. And if that patient gets sick, there is no law that would
allow me to force testing on that patient for a possible xenogenic infection.
And there's no law that would prevent that patient from coming to any hospital
in the United States and demanding and receiving therapy. So there are many
layers to how individual patients could frustrate our very best attempts to
ensure the safety of this new technology.
What is the right moment to confront the ethical issues involved in this?
Is it before we do clinical trials?

The problem with taking a new technology and examining in detail the ethical
issues before the new technology can really be implemented in human patients is
that it is, in some ways, critical, but it is premature. It's premature to
delve into the ethics before we can define the dimensions of the new
technology, before we even can define the risks of the new technology.

The ethical debate has to have some of the same principles as the scientific
debate: These are the facts as we know them; this is what we can say about the
ethical universe that we confront with this set of facts. We know that these
facts are changing, and we will be there to reexamine new facts and be flexible
about the ethical decisions that we make as these new facts unfold.

That's the nature of a new technology. One has to be very cautious that we
balance the critical importance of maintaining safety -- public safety and
patient safety -- against the tremendous promise of a new technology. If you
regulate the technology out of existence before the technology has shown any
evidence of its promise, then you've robbed future generations of a tremendous
boon.
What about the conflict of interest issues?

One of the major challenges in the development of a new technology is to sort
through the potential for conflicts of interest. It is now becoming very clear
to all of us--to the public, to the regulatory agencies, and to physicians and
scientists -- that we have to account for conflicts of interest before
responsibly going forward to clinical trials and new technologies. Principal
investigators cannot own the patent on a particular new technology. Principal
investigators can't have significant holdings of stock in a company that will
benefit dramatically. Principal investigators shouldn't be highly paid
consultants of companies. There has to be some objective group overseeing
these studies at the level of patient-to-physician contact.

The dynamic here is that you certainly don't want to go forward in clinical
trials, in brand-new cutting-edge technologies, without physicians and
scientists who are absolutely involved in the genesis of these scientific
discoveries. So it's very important that we don't create a situation in which
no one can be involved in the trial that owns a patent, that has a stock right,
who is a consultant for the company. That's not at all what I'm saying. They
have to be involved in the trial, because they're the experts in the trial.
You can't pick an internist out of the general medical clinic and say, "Hey,
you've got no interest in this trial, you're great, you're going to run this
trial in gene therapy," or, "You're going to run this trial in
xenotransplantation." That's ridiculous.

What I'm saying is that we have to acknowledge the potential conflict, create
safeguards within the design of the trials, and then monitor them well. And I
think we can do all of those things, and do them well.
Currently, aren't some of the key players -- the principal investigators --
also stockholders of companies that stand to gain tremendously? And isn't
there a question of perception that one needs to be careful about?

At the present time, the reality is that, in a number of proposed clinical
trials, the principal investigators have been the developers of the
technology, the patent holders, the owners of the company that's developing the
technology, or consultants to that company. And therefore they have tremendous
amounts of vested interest, financial and otherwise, in the success of these
trials.

However, you have to therefore have physicians involved in the trial who
have nothing to do with the profits, have nothing to do with the patent, and
nothing to do with the company. And they have to have a dynamic and productive
interaction with these scientists and physicians that do other vested
interests. Achieving that balance, and doing it safely and monitoring it well,
is what the big challenge is right now, for going forward responsibly in these
clinical trials. The way we'll do it is through institutional review boards,
and through regulations at the level of the Food and Drug Administration ...
process. And that's all in play right now.

We recognize the limitations of that. We recognize the fact that that is not
part of our agreement with the public. And specific changes in regulations are
now being discussed at the level of local institutional review boards, which
are responsible for approving and monitoring any of these studies, and also, at
the federal level, at the level of the FDA ... process.
What are some of the issues about the virus?

In simple terms, a virus is a small packet of genetic material that's
essentially packed tightly in a particle, and that particle can be transmitted
to a human cell. When it gets into the human cell, it actually incorporates
itself in the human cell's own DNA. If the infection by this viral particle is
successful in getting into what we call germline cells, then all the children
that result from that individual will contain the viral DNA forever.
What's a retrovirus?

Everyone is aware of the fact that there are many different kids of viruses.
We know about the flu viruses, we know about the cold viruses. Retroviruses
are one group of viruses that are distinguished by the fact that they
essentially have to make their own DNA after they get into the human cell. So
they inject themselves into the human cell, and then they have special enzymes
that they bring along with them, that reverse transcribe --retro-- the RNA into
DNA. That DNA is then inserted into the human cell's genes, into the human
cell's chromosomes.
Is part of the idea here that, unlike some viruses, there are certain
viruses that end up replicating themselves through generations and become part
of the basic DNA make-up of an animal?

Right. I think that one of the special concerns over viral infection in
xenotransplantation is . . . over retroviruses. . . . If, in the process of
inserting themselves into the host cell's chromosomes, they insert themselves
into germline cells -- sperm and egg -- then all the progeny, all the children,
of those individuals will carry this infection virus into the future. That's
the special aspect of the infectious disease risk we're facing in
xenotransplantation now.

Another unique feature about this group of retroviruses is that, when a
retrovirus infects a cell and inserts itself in the cell's chromosomes, it
actually blocks infection by any other retroviruses. What's happened in the
process of incorporating retroviruses into germline cells, so that they're
passed along, now, in the species in perpetuity, is that these offspring are
actually resistant to the virus.

What we come to understand is that these germline-incorporated viral DNA
particles are actually the reflections of ancient plagues that, after
decimating perhaps hundreds and thousands of individuals within that species,
finally became incorporated in the germline, leading to offspring that were
resistant to the infection.

The irony of all of this is that the success of the species in incorporating
these viral DNA into the chromosomes and creating subsequent resistance is that
it doesn't create resistance if you now take those cells and transplant them
into another species. So you protect the species -- in this case, let's say,
we're protecting the pig -- but if you take the pig cells now and transplant
them into a human patient, there's nothing protecting the human patient. So
that virus now can come out and infect the new species.
How does a virus get passed out into the next generation?

Retroviruses incorporate themselves into the host cell's chromosomes. Imagine
that sperm and egg cells, which are just another form of host cell, are each
infected with the retrovirus, and each incorporate the retrovirus into the
chromosomes. Then any fusion of egg and sperm to generate a child will carry
the two copies of the infectious chromosome into the child. And that's every
cell in the child. So when that child gives rise to children, that viral DNA
will be incorporated faithfully in that child and into the children's children
and on, in all generations, in perpetuity.

Viruses are very small infectious particles, and essentially, if we think about
their job, it's to get themselves inside a cell that's permissive for them to
survive. And then they actually reproduce themselves in great number, infect
other cells, and therefore carry on.

Some retroviruses in this process actually are successful in getting themselves
into germline cells -- the eggs and the sperm -- that basically carry on our
genetic traits to the next generation. If they're successful in getting into
this germline, this basically a free ride for this cell, because it then is
carried on to all future generations in that species.
How would that work?

Let's start off with understanding that all pig cells carry multiple copies of
infectious virus. That infectious virus is not dangerous to the pig, but there
are no such rules for humans. We already demonstrated in the laboratory that
that infectious virus infects human cells. And we know that when you move an
infectious agent from its host environment -- in this case, the pig -- and put
it in a completely new host environment -- in this case, a human patient after
a transplant -- that there is no way to predict the pathological consequences.
There's no way to predict what kind of disease could be produced when this pig
virus is accidentally transmitted and becomes infectious in the human
patient.

Indeed, there are many examples in which viruses that basically are carried by
certain animals and cause no disease in the animals, when transmitted to
humans, can be deadly. A really good example of this is the hantavirus. It's
carried by an innocent little deer mouse. And the deer mouse is absolutely
healthy. If a human gets infected with that very same virus, there's a 70
percent death rate in these human patients.

Take Ebola virus for another example. There's no evidence that any monkeys are
sick with Ebola virus, but if Ebola gets into a human patient, there is 75
percent, 80 percent mortality, and it's a horrible disease.
If a pig virus got into a human, how would it manifest? What would you see?
What kind of disease would be involved?

What we know about the family of viruses that are closely related to the virus
in the pig that we're concerned about is that they all produce lymphomas and
leukemias. These are cancers of the blood system. And if we saw activation of
this pig virus in human transplants, we predict that we would also see the same
sort of spectrum of blood cancers -- leukemia, lymphoma. There is going to be
a lag time between the moment of infection and the production of this possible
cancer. And during that lag time, we are going to have to rely on very
sensitive molecular diagnostic tests to detect the replication of the virus
before we see the evidence of the leukemia or the lymphoma or any sort of
cancer from these patients.
Let's say that someone has received some sort of xenotransplantation. What
would have to happen for there to be a disease at the end of the process?

A series of steps would have to occur to produce any kind of disease after
transplantation of an infectious agent, like a virus, from an animal organ to a
human. First of all, the virus has to get into the human cells. There has to
be basically a receptor on the human cells that recognizes that virus and
mediates that viral infection. Then there has to be mechanisms in the virus
that allow it to be reproduced in large numbers and released by the infected
cell. There is only any real risk with release of new particles of infectious
virus, the new generation of cells, and the spread of the virus, in what we
call an active or a productive infection.

So one could conceive of several different things occurring after
xenotransplantation. We could imagine the possibility that there might be no
infection of a human cell. In other words, the virus in question just does not
have the ability to see, in fact, and enter a human cell. That would be great.
It's possible that we may have viruses, like the retroviruses we've been
concerned about in pig cells, that we do know can get into a human cell.

They can get into the human cell and cause infection. But then . . . if they
don't replicate actively and spread to subsequent cells in the patient, you
don't have active infection; you don't have productive infection. That
wouldn't be likely to produce any kind of disease. The infection could then
simply go dormant. And there are many viruses already in humans that we know
get in, replicate once or twice and go dormant, and you then carry them for the
rest of your life with no consequences at all for disease.
What do we know so far about these pig viruses? How active and aggressive
do they seem to be?

What we know about these pig viruses today is that, first of all, they do
infect human cells. Secondly, under certain circumstances, they can actively
infect human cells. In other words, they can infect a human cell initially,
replicate themselves, and spread to other human cells. So that's part of why
there's a real concern.

However, in other types of primary human cells, the virus may get in or not get
in at all. But in either case, it replicates very poorly, doesn't spread, and
doesn't produce active infection. In the animal work that we have done and
published, pig virus was identified in the animals. It infected animal cells
in the transplanted animals, but it never produced an active or productive
infection. It appears to have gone dormant very early in the process.

So at the present time, the evidence would suggest that, number one, there's a
real risk of infection cells; number two, there is a possibility of productive,
active infection. However, that risk would appear to be relatively low, based
on what we know today.
You've infected mice with pig virus?

What we set out to do was to determine whether or not we could infect an animal
after transplantation of pig islet cells. . . . A major question is whether
the transplantation of pig cells or tissues would result in the production of
infectious virus in a transplanted situation, and whether that virus would get
transmitted to the transplant patient. We transplanted pig cells into mice
that have a very profound immune defect. This was done as a worst-case
scenario -- a patient who had no immune response against the pig cells. What
we found was, first of all, that pig cells continued to produce infectious
virus after the transplantation. In fact, actually, pig cells transiently
increased their production of virus, due, we feel, to the stress of the
transplant on these cells.

Secondly, production of the virus continued for as long as we followed these
animals, so that we had animals out over three months. These pig cells were
still producing virus. The lesson to us is that successful pig cell or tissue
transplantation will expose this patient to a constant low-grade production of
infectious virus.

The second thing we found is that, in that circumstance, some of these virus
particles actually infected mouse cells -- we got infection. This was the
first example of infection of living cells within an animal following a pig
tissue transplant, and therefore is, if you will, a proof of principle for the
disease-producing potential -- the infection production potential--in pig
virus.

The good news is that none of our animals were sick. In fact, our evidence
suggests that the virus, after a replication or two, basically went dormant;
didn't spread to other cells within the mouse. Therefore, as a concept of what
the dimensions of the risk are, we can say that, at least in the current time,
in this model, we have infection, but we don't see active, productive spreading
infection. And that's somewhat reassuring at this time.
What do the mice experiments lead you to believe?

Based on what we found in the mouse experiments, we predict that if we put
virus, or pig cells, into non-human primates, that we will also see infection
of cells, production of virus, long-term. And we would predict that we will
not see productive active infection but rather, the same sort of process of
dormancy that we saw in the mice. And we need to test that.
And therefore, what is the likelihood at the moment for this kind of
infection in humans?

If our conclusions from the mouse model are correct and the disease indeed goes
dormant, the risk of this particular pig virus for human transplants will be
relatively low. Now, there's always a danger that a virus entering a whole new
world--going from a pig to a human--will undergo a mutation or mutations that
will totally change that virus's potential for spreading and potential for
causing disease. And that's the big unknown. It's one thing to do 20 mice or
40 mice; it's not a lot of mice. It's another thing entirely to do 100,000
human patients a year.
What did your work show for the first time?

The importance of the work that we published recently was demonstrating for the
first time that in an animal model of transplantation, the simple
transplantation of pig cells, prepared and transplanted in a way that would be
done in a clinical trial of transplantation of pig cells,

A principle for gene therapy--just to put this into context -- is that you
would never allow exposure of a patient to what is called "replication
competent" or infectious virus. Yet what I've just got done telling you is
that transplantation of pig cells in our immune-deficient animal evidenced very
clear, ongoing chronic production of infectious virus.
When you transplanted pig cells into immunosuppressed mice, how did that fit
into the bigger picture?

When we were deciding how to create this animal model for transplantation, we
chose a severely immunocompromised, or immunodeficient mouse. This is, in some
sense, a worst-case scenario. There is no immunity in this mouse to kill a
virus or reject an organ.

Yet what you have to understand is that a successful pig cell or pig organ
transplant, by definition, means that you've come up with a strategy to prevent
any sort of immune response against pig cells or tissue. So in that sense, the
use of a severely immunodeficient animal that can't reject the pig cells is
perfectly reasonable. . . . Well, that part's true, but you still could allow
the animal, or the patient, to reject or kill the virus; a failure to reject
the organ isn't the same as a failure to reject the virus. And that's a
reasonable point. However, it turns out that many of the genetic engineering
strategies currently being proposed would also significant inhibit the ability
of the immune system to target and kill the virus.
What do you hope to do next?

Based on this work in the mouse model, it is our plan to continue the work
forward into non-human primates, as a much closer model for what would happen
when pig cells are transplanted into human patients. This is particularly
relevant, in that the criteria established by the Food and Drug
Administration's expert advisory committees for allowing the first clinical
trials to go forward in human patients has been survival for six months or more
in non-human primates.

So we're going to have access to non-human primates being transplanted as the
basis for establishing the first clinical trials. And so the idea that we
would, at the same time, also pursue these experiments of potential infection
risk in these same animals is obviously a very attractive, very reasonable,
very ethical way to move forward in protecting the public from the risk
issue.
What happened to the trials . . . when this kind of virus was discovered?
How did people react?

When evidence first appeared that the pig virus that we were concerned about
could infect human cells, and that those human cells then would produce more
virus and infect other human cells, the FDA immediately put a hold on
xenotransplantation trials in the United States.

What then followed was a series of very high-level meetings, over a period of
about a year, in which experts of all sorts from both sides of the Atlantic
came together at the National Institutes of Health, at the Food and Drug
Administration, and with the Centers for Disease Control in Atlanta. The
meeting was to discuss specifically what we could do to ensure the safety of
this new process in a clinical trial. The focus of those discussions was the
development of accurate, sensitive, new molecular diagnostic techniques that
could say if a patient was infected with virus.

When those trials of new diagnostics were completed and presented to these
expert advisory committees about a year after all this happened, it was felt
that so much significant progress had been made that it satisfied the criteria
for allowing the hold to come off and for the trials to continue. In the
meantime, things didn't just stop there. What's fascinating is that a number
of biopharmacy companies, including major pharmaceutical support from Novartis,
went forward and did a trial of every patient that they could get tissues and
blood samples from, in the history of xenotransplantation, that had been
exposed to pig cells. And they came up with 160 patients.

When this was analyzed in detail by company scientists, in close collaboration
with government scientists at the US Centers for Disease Control and at the
Food and Drug Administration, it turned out that there was no evidence, in any
of these 160 patients for infectious transmission. Pig virus was not seen in
any of those patients or in any of the cells.

There are flaws in any sort of what we call a "look-back" study, a
retrospective study, so this doesn't solve it, and doesn't prove that this is
safe. But it is very important evidence to reassure scientists and physicians
and regulatory agencies and the public.
What are the statistics on the organ shortage now?

There are approximately 60,000 people waiting for a kidney transplant in the
U.S. There are about 20,000 people each waiting for heart and heart and liver
transplants at any given time. And you understand the number is smaller for
the liver and heart transplants, because the sad truth is that those patients
are dying before they get the organ transplant. The kidney transplant patients
being listed at least can survive on dialysis.
Can you talk about that patient who's very desperately ill, and their
willingness to take the risk of getting a pig virus? What's involved in that
decision for them?

For an individual patient who's facing the possibility of a xenotransplant, we
really have to think for a minute about what that patient is facing in terms of
the chance of living and dying. For a patient with a failing kidney, a failing
heart, a failing liver, they're really looking at either a profound loss of
their ability to function and enjoy their life and even death, in the case of a
heart and liver and lung transplants.

There are a lot of things that people are willing to accept as risks in the
setting of being desperate enough to be basically at the door of death. For
that patient to accept a xenotransplant, they're going to, right now, accept
some risk of transmission of a new infection. We think that, based on the
family of viruses that these pig viruses belong to, that that new infection
would probably be some sort of blood cancer--leukemia, lymphoma, maybe a tumor.
That patient will also accept the fact that there are unknown pig viruses and
other pig pathogens that we can't predict. So there could be diseases that we
cannot anticipate.

Another critical thing is that there'll be new immunosuppressive drugs and
strategies. The traditional human-human organ transplant cocktails are not
sufficient for xenotransplantation. So there really are going to be a whole
series of challenges and risks for that patient to comprehend prior to agreeing
to participate in the first xenotransplant trials. The bottom line, though, is
if it's life and death, there's going to be a lot that patients will be willing
to agree on, if they're assured of any reasonable benefit.
What about this question about the patient's risk versus the public's
risk?

The history of medical and clinical research has dealt for many, many years
with the risk to the individual. What's really somewhat unique in this new era
of biotechnology is the risk to the public.

A patient and a patient's family can discuss in an informed way, and accept in
an informed way, personal risks -- risk of an infection, the risk of a tumor,
the risk of dying. A patient and a patient's family cannot accept risks for
the public. They can't accept risks for you or for me, for your children, for
my children. So this new element of the public risk of the new technology
changes the whole nature of the consent as we know it today.
How do we get to that consent? The new features, the new challenges to the
consent process are presently under quite a bit of debate, both at the federal
level, in Congress; and at the regulatory level, at the FDA; and it should be
brought forward to a similar level of debate in the public. What can you
do?

Well, I don't know. I really have no idea how, at this point, one can
intelligently make a decision on the consent form for a public health risk,
when the truth is that we can't quantify the dimension of the risk.

Moreover, when we think about a consent form and these issues, we're really
talking about all of new biotechnology; we're not talking about the pig virus
risk. So even if tomorrow I would feel comfortable sitting here and
quantifying for you the risk of a pig virus, these questions about the public's
risk in a consent form that an individual signs go way beyond anything to do
with a pig virus. It goes way beyond xenotransplantation. It extends to all
new biotechnologies.

So I don't know if specialists in some of these new technologies, like myself,
can really know where the public wants to go, where the federal government
wants to go, in constructing a consent that works for everyone -- a consent
that guarantees reasonable consent for a new biotechnology for a public that's
worried about its impact.

With that said, admitting that this is a difficult area, it's critical that we
don't regulate a promising technology out of existence. If we take a position
like that, if we say, "There's a risk, therefore we can't do it, we can't allow
it, we can't develop it," then the history of medicine ends right there, on
that day. There's no future, because nothing that's ever occurred in medicine
had no risk.

Think about the early vaccine trials. Can you imagine trying to explain to
someone when Edward Jenner inoculated cowpox into individuals at the turn of
the century, that they weren't going to get sick, and there was no risk that
the virus would spread and mutate and all these things that we're talking about
in the context of xenotransplantation and infection risk?

But yet, the miracle was that he did it, and created the first functional
vaccine for smallpox, and the effect on public health was absolutely
remarkable. The polio vaccine . . . just think about the millions of children,
worldwide, who've been spared the devastation of polio. Was there a risk with
the early polio vaccines? Not only was there a risk, there were complications.

So we need to make sure that the public understands that medicine moves forward
through some risk. The public should be involved; the public should think
about it; the public should participate; but they shouldn't overreact. They
need to be reassured that there is a future here, that we're going to do this,
that we can do it safely, and we can do it with a remarkable benefit to human
beings in the future. It's worth some risk.
And what about this new dynamic of the companies' and doctors'
involvement?

One of the things that is really unique about this new biotechnology is that
you have physicians and scientists who've made discoveries in their own
laboratories, who have realized some of the dramatic potential. Then they've
gone out, patented those discoveries, created companies, sold companies to
large pharmaceutical companies, all of whom see that with a tremendous
clinical success would come tremendous potential for making money.

And now, you're sitting there with all of this investment, all of this
potential conflict of interest, and these are the experts who are ready to move
these things forward into the final clinical trials that define this whole
system. And it's quite a remarkable irony. On one hand, these are the people
who have to be involved in these clinical trials. You don't want clinical
trials done by people who have no idea. You want clinical trials done by the
people who really did it hands-on. Yet these very people are conflicted now by
owning the technology in some way or shape. How do you deal with it? How do
you deal with this responsibly? How do you assure the public that these
experts, who are so important in this last step -- application to clinical
trial -- don't do anything to ensure their private interest? It's not easy.
It's a real issue.

At the federal regulatory level, there are now rules being made that these guys
should be involved in the trials, but not be the primary overseeing supervising
investigator. Involved hands-on in the trial, but other scientists, other
physicians, who have no personal financial interest, are making the day-to-day
decisions, are talking to the patients, looking at the data, communicating with
the regulatory agencies, communicating with the institutional review boards.
That's the way we're going to deal with this intersection between these
scientists and physicians with special interests. And there is this absolute
requirement that they be directly involved, in some way, in these clinical
trials.
And how do we answer those physicians who are saying, "You can debate this
in the public all you want. Just know that every few minutes you do,
somebody's dying." How do you answer that passionate argument?

I don't think you counter a passionate argument by physicians who are concerned
that unreasonable, unnecessary delays in bringing promising new technologies
forward results in patient death, patient suffering, lives lost, families
disrupted. There isn't any reason to argue with those physicians. They have
to be heard. They have to be balanced by a reasonable approach to initiating
these trials that reflects a serious understanding and concern for public
safety, now and in the future. They have to be balanced by a reasonable
scientific potential for benefit. To do it just because the disease is
horrible isn't an argument to do something that has no potential for success.
When I listen to these passionate arguments for patient care, my response is
that that's a very appropriate thing to keep in mind every time I think about
this area.

And every time I think about this area, I feel equally responsible to be
concerned about the safety to the public, the safety to the patient, the safety
to future generations.

. . . And it should be expected that there is a reasonable benefit potential
for the patient before you go forward to a clinical trial. The idea of just
doing a clinical trial because the patient's sick or dying is not enough, no
matter how passionate and compassionate I feel for that patient. There has to
be a reasonable benefit. The idea of saying, "Well, there's no reasonable
benefit right now, but I'm going to learn something," isn't the best argument
in the world, either.
Is there a bit of hype in xeno now?

A few years ago, I would have been more concerned that certain groups in this
area of xenotransplantation were hyping the future of xenotransplantation a
little too hard. . . . I think the wind is out of the sails, for the moment,
on xenotransplantation. Everybody realizes its tremendous potential, and
there's continual and very active, work underway to bring this to a real
clinical therapy. But I think it's pretty well founded in reality today. I
don't think it's being hyped. And I think there are very powerful forces
opposing xenotransplantation clinical trials, both in Europe and the United
States, and Canada, that are insisting on benefit; are insisting on reasonable
awareness of public risk; are insisting on consent forms that are done
privately; and public discussions.

Right now, I would honestly say it's fairly well balanced. The extremes are
well represented by articulate physicians and scientists on one hand, who see
the promise and are compassionate about their patients, and other groups that
see the possible risks and have done a good job of articulating it publicly.
Why are pigs the best model?

Pigs are presently used in great numbers throughout the world for food and
other products, such as leather. Therefore, there is excellent knowledge of how
to raise pigs, how to keep them healthy, what kind of diseases they have.
There are tremendous amounts of resource for pig breeding, pig engineering. We
can now clone pig cells. So there are many, many good reasons why the pig has
kind of emerged as the first major animal species. They breed several times a
year, with multiple children in every litter, so it's relatively easy to
quickly expand a pig herd.

With that said, though, there are potentials of doing some of this work in
sheep, some of this work in goats. Some transplants could even be done with
cattle, and there are cloning technologies available for each of these other
species. So it's important in perspective to say that the pig has got a number
of very compelling reasons to be the first commercial species to be exploited
for xenotransplantation, but that there are also potentials for specific other
species to be used as well in the future.
What is the model here? Is it new that in fact we're really talking about
new mechanisms for something that's related to a new technology, rather than
what we traditionally think of as human to human transplant? After all,
they're trying to make a product, make it reliably and plenty of it. Can you
just explain that?

One principle behind biotechnology is that you actually make a product, and
take the product and make a profit. It's in that context that one can
understand the interest in using the pig as the first species for
xenotransplantation. Pig farming, if you will, has been going on for
centuries, across the world. We're very good at caring for pigs. They
reproduce well. They're relatively cheap to house. And we've become quite
comfortable with the commercial use of pigs for a number of different
things--food and other products. So it's really a very logical commercial
venture to do in the pig.

And I think that's why the focus has been on the pig. The dramatic success
with cloning pigs extends significantly the kinds of genetic engineering that
we can now do on the pig. Before, we were able to knock new genes into the
pig. But now we can also knock genes out of the pig. And so the pig now
becomes even a better species for this sort of biotechnology commercial
venture.
It's ironic . . . that our efforts to try to knock out a sugar in the pig .
. . may make it easier for the viruses that they carry to reproduce.

Right. It's very important to consider that, with every new strategy to
improve xenotransplantation, we have to reexamine its possible impact on the
infectious disease risk there. One good example of this is that hyperacute
rejection of a pig transplant is mediated through a special kind of sugar
that's expressed on the cell surfaces of most pig cells. It makes sense, then,
that if one wanted to avoid hyper-acute rejection, that a target for genetic
engineering would be to remove that sugar and transplant pigs that don't have
that sugar. There should be much less or no hyper-acute rejection. Great
idea.

The problem with that, from an infectious disease point of view, is that when
the pig virus comes out of the pig cells and looks around now to infect the
cells around it, it carries with it these pig sugars. Now, the human immune
response sees the pig sugars on the pig cell and kills it; it sees the pig
sugars on the virus and kills it. If you remove the pig sugar from the pig
cells--because that's a great idea for hyper-acute rejection--the consequences
of it for the infection is you also remove it from the virus. Therefore, you
basically hide the virus from the human immune system. Obviously, that's not a
good idea, from the infectious disease point of view.

So that's the kind of dynamic that we're going to have to face. Advances
intended to improve success of the xenotransplant procedure itself may have
unintended negative consequence for the viral infection issue.
So, if you wanted to design . . . a way for the virus to spread, you could
almost do nothing better than to create this knockout effect, right?

This is a very serious increase in the potential risk of spreading this
infection, to the extent that removal of this set of pig sugars from pig cells,
and therefore its removal from the surface of the viral particles, really masks
the virus from the immune system.
What about the Baby Fae case?

One major very public event in the history of xenotransplantation was the Baby
Fae case. In that situation, an infant was born with basically a life-ending
defect in the formation of the heart. And to make an effort to save the life
of this young baby, surgeons performed a dramatic transplant between a young
baboon and this child.

It got worldwide publicity. Number one, it was obviously very dramatic; number
two, it was an infant, and, if nothing else defines the real cutting-edge of
new technology, it's our children. The results were that this baboon's heart
functioned for several weeks, maintaining this infant alive, before failing.
And that also captured the imagination of the world.

In the history of xenotransplantation, the Baby Fae case will be judged
differently by different people. In my opinion, it was, at least, a very
powerful proof of the concept that you could take an animal organ and save the
life of an infant, an innocent child who was born without a functioning heart
and who would die. So in the history of xenotransplantation, in my view, this
was a very important event.

To others, it was an also an event that demonstrated that three weeks of
function of a baboon heart in an infant is not the level of benefit that we
would expect to justify, today, a clinical trial. And I also agree with
that.
Eight years later, Tom Starzl takes the next step. What did he do?

Several years later, another major event in the history of xenotransplantation
took place, when surgeons in Pittsburgh transplanted baboon livers into several
patients under full immunosuppression. And those patients also lived for two,
three months with function of the liver transplants. And yet all of then,
again, eventually failed. Many of the patients succumbed to overwhelming
infection, because the level of immunosuppression that was required to keep
these livers from rejecting was so great.

Proof of concept? Well, again, it's a proof of concept that these patients
survived, and that these non-human baboon livers did function in these patients
for weeks, successfully, and kept these patients alive.

In the end, the surgeons at the University of Pittsburgh concluded that,
despite the fact that this was a powerful proof of concept, that our inability
to keep these patients alive with a functioning baboon liver for more than
several weeks was still a barrier to going forward with any further clinical
trials. And they themselves put their further plans on hold, until the
technology would move forward to such a time that we'd have better benefit.
How much has been invested in this? The term we hear talked about is that a
billion dollars has been invested in xenotransplantation.

To date, a reasonable estimate for the kinds of dollars that have been invested
in xenotransplantation to date, is somewhere between $600 million and a billion
dollars. Now, that's against a projected market that, worldwide, could be
between $8 billion and $12 billion a year. So it's a pretty good investment,
so far, for those sort of dramatic returns.

If successful xenotransplantation is achieved, the first group that benefits is
all our patients, and that's fundamental to keep in mind here. The profits
will be humongous, but they'll be based on its applications in a dramatic
spectrum of different diseases, leading to all kinds of important advantages
for patients.

Now, reality-wise, the dollars will be earned by a handful of very large
international pharmaceutical companies; they will be earned by a number of
small adventurous biotechnology companies that have contributed to different
important stages in the achievement of this. And I think it's very important
to also point out that it'll open up incredible opportunities for new
biotechnology companies and new strategies to take advantage of.

It's so very important to remember that all of this new technology is a
continuum. You go from xenotransplantation to cell transplantation to gene
therapy. The opportunities for future companies, for future scientists to come
up with new technologies and to take advantage of this tremendous new market,
is very real.
And what's unique about this new biotechnology?

What is unique is it is such a complex mix of different fundamental new
technologies. Biotechnology doesn't succeed on a single molecule, on a single
gene, on a single process. It's not like the old days, when you had bacteria
and you made an antibiotic like penicillin and it killed the bacteria and you
had a blockbuster drug.

Biotechnology is actually something that, to be successful, mixes dozens of
different technologies eventually. That means that the final success of a new
biotechnology may involve dozens of companies in achieving the final, refined,
successful strategy that works to cure human disease.

And as a result, the rules are new. There are scientists who actually did the
basic work in their own laboratories, and then, along with their institutions,
have gone on and taken the patents out. Then they've taken those patents and
they've started their own new companies, which then have brought in investments
from large pharmaceutical companies. So now you end up with these really
complex collaborations between basic scientists, academic institutions, the
universities, the private research institutions--who own the patents, and who
have equity interests in the companies that have been formed. The scientists
and the physicians have equity interests. They're consultants. They have
these big pharmaceutical companies which are overlooking them and have put in
hundreds of millions of dollars.

I don't think there's ever been a situation in which things have been this
complicated. And now the complexity will increase all that much more, if you
think about the fact that one of those companies is going to have to get
together with half a dozen companies in order to get the final successful
product,
What else is unique about xenotransplantation?

If we look at the history of organ transplantation, there's another feature
that's very unique to xenotransplantation, and that, namely, is the profit
motive. Human to human organ transplantation is done without any money being
paid for the organ. By federal law a donor organ cannot be sold. Can't be
done. You can pay a professional fee to harvest the organ, but you can't sell
the organ in any way, shape or form--it's against the law.

Xenotransplantation is the total opposite. These companies will own these
animals. They will own the organs. And they will sell the organs and make a
profit. It's a completely different paradigm for organ transplantation and
cell transplantation.
What about the costs per patient for these procedures?

There's been a lot of discussion about what would be even reasonable to charge
for a pig kidney or a pig heart. And that would be based on the companies
involved, that that charge would allow them a reasonable profit. At the same
time, government agencies and healthcare plans . . . need to see it as being a
reasonable charge to be able to do anything widespread . . . on a clinical
level.

So, based on these sort of models, a reasonable charge for organs has been
bantered around, somewhere around $40,000 to $50,000 for an animal organ. And
these are speculated charges, because we're not going to know what they're
going to cost until the day they have them to transplant.
Is it evil?

No. There's nothing evil in companies investing hundreds of millions of
dollars of investment in bringing a new technology forward, not to speak of
hundreds of thousands of hours of hard work by their employees, and then
expecting to make a profit. Why is that different than a semiconductor or a
new technology applied to cars, or any such example in new technology?
Will there be a pig farm on the other side of my hospital now?

That's a fun question. One of the many challenges that faces the whole field
of xenotransplantation, if and when it becomes a successful tool, is exactly
how to handle the movement and harvest of these animal organs and tissues from
the herd to the patient. Some organs and tissues can be harvested at distant
points and shipped. So companies now are thinking in terms of models in which
they would have special facilities matching special herds, and then you would
essentially get organs and tissues on order.

And the coordination then would be that I bring a patient into the hospital at
a given date and time, with the idea that it would be coordinated with delivery
of the organ or tissue that I need for this patient's transplant, in a timely
fashion, clean, healthy, ready to go into my patient.

In other circumstances, these organs or cells are not going to be shipped; they
won't be able to be shipped. In which case, it does raise the very interesting
situation in which a biotechnology could never afford to have a herd and a
production facility in every single city in the whole United States or in the
world. And then what do you do?

So it raises some interesting challenges about whether hospitals and
institutions would either have to pool resources, so each city would have a
central resource for doing xenotransplantation. Or it's even possible that
they'll accept the responsibility that every hospital will have to have some
sort of xenotransplantation preparation facility. And how that's going to be
supplied, and how that's going to be billed, is way beyond anything I can
speculate on.